Metabolic diseases, including diabetes, are increasing recognized to be influenced by complex genetic factors involving multiple organs and molecules. A single important molecule may directly or indirectly control the function of other molecules and multiple tissues. The function of an adult tissue is clearly dependent upon its history, i.e., its differentiation and development, as well as upon signals emanating from other tissues and the environment. This Program Project Grant involves six outstanding investigators, each focused on a specific molecule that regulates development and metabolic function a specific tissue. (Lazar) addresses the role of the nuclear receptor PPAR-gamma in adipose tissue development and type 2 diabetes. (Stoffers) examines the role of the homeodomain protein PDX in pancreas development and glucose metabolism, especially in the context of maturity onset diabetes of the young (MODY). (Silberg) investigates the role of the homeodomain factor CDX in the development and adult proliferative and nutritional function of the intestine. (Kaestner) addresses the role of the HNF3 family of winged helix factors in liver development and glucose metabolism. (Birnbaum) studies the role of Akt/PKB in the regulation of beta cell growth and function. Each individual project addresses an important hypothesis using molecular and genetic tools, including in vivo mutational analysis. The particularly exciting aspect of this proposal is its tremendous potential for synergism. Frequent interactions will maximize the opportunities for new discoveries related to obvious or surprising interactions between this variety of molecules and multiple metabolic tissues. These interactions will be facilitated by a collaborative environment at the University of Pennsylvania; the close physical proximity of the investigators; an administrative core that coordinates frequent meetings among the investigators and with scientific visitors; an outstanding morphology core in a dedicated central space that encourages physical interactions and cross-pollination via the technical director and shared personnel; and an embryonic stem cell core that facilitates interactions and rapid dissemination of new results, techniques, and ideas. The proposed studies will address major and specific questions relevant to diabetes, metabolic, and nutritional diseases. At the same time, the specific investigators, environment, and format of this proposal facilitate interactions that should enhance the discovery process. The likely and potential discoveries will impact on diabetes, obesity, and other complex metabolic diseases that ravage our society.